There are 15.7 million people or 5.9% of the population in the United States who have diabetes. While an estimated 10.3 million have been diagnosed, unfortunately, 5.4 million people are not aware that they have the disease. Each day approximately 2,200 people are diagnosed with diabetes. About 798,000 people will be diagnosed this year.
Diabetes is the seventh leading cause of death (sixth-leading cause of death by disease) in the United States. Based on death certificate data, diabetes contributed to more than 187,000 deaths in 1995. Diabetes is a chronic disease that has no cure.
Many people first become aware that they have diabetes when they develop one of its life-threatening complications. Diabetes is the leading cause of new cases of blindness in people ages 20-74. Each year, from 12,000 to 24,000 people lose their sight because of diabetes. Diabetes is the leading cause of end-stage renal disease, accounting for about 40% of new cases. In 1995, approximately 27,900 people initiated treatment for end stage renal disease (kidney failure) because of diabetes. About 60-70 percent of people with diabetes have mild to severe forms of diabetic nerve damage, which, in severe forms, can lead to lower limb amputations. In fact, diabetes is the most frequent cause of non-traumatic lower limb amputations. The risk of a leg amputation is 1540 times greater for a person with diabetes. Each year, more than 56,000 amputations are performed among people with diabetes. People with diabetes are 2 to 4 times more likely to have heart disease which is present in 75 percent of diabetes-related deaths (more than 77,000 deaths due to heart disease annually). They are also 2 to 4 times more likely to suffer a stroke.
Diabetes is a disease in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar, starches and other food into energy needed for daily life. The cause of diabetes is a mystery, although both genetics and environmental factors such as obesity and lack of exercise appear to play roles. There are two major types of diabetes, Type 1, which is an autoimmune disease in which the body does not produce any insulin, most often occurring in children and young adults, and Type 2, which is a metabolic disorder resulting from the body""s inability to make enough, or properly use, insulin. People with type 1 diabetes must take daily insulin injections to stay alive. Type 1 diabetes accounts for 5-10 percent of diabetes. Type 2 diabetes is the most common form of the disease accounting for 90-95 percent of diabetes. Type 2 diabetes is nearing epidemic proportions, due to an increased number of older Americans, and a greater prevalence of obesity and a sedentary lifestyle.
Impaired glucose homeostasis (or metabolism) refers to a condition in which blood sugar levels are higher than normal but not high enough to be classified as diabetes. There are two categories that are considered risk factors for future diabetes and cardiovascular disease. Impaired glucose tolerance (IGT) occurs when the glucose levels following a 2-hour oral glucose tolerance test are between 140 to 199 mg/dl. IGT is a major risk factor for type 2 diabetes and is present in about 11 percent of adults, or approximately 20 million Americans. About 4045 percent of persons age 65 years or older have either type 2 diabetes or IGT. Impaired fasting glucose (IFG) occurs when the glucose levels following an 8-hour fasting plasma glucose test are greater than 110 but less than 126 mg/dl.
The total annual economic cost of diabetes in 1997 was estimated to be $98 billion dollars. That includes $44.1 billion in direct medical and treatment costs and $54 billion for indirect costs attributed to disability and mortality.
The direct and indirect costs of diabetes are high. In 1997, total health expenditures incurred by people with diabetes amounted to $77.7 billion, including health care costs not resulting from diabetes. The per capita costs of health care for people with diabetes amounted to $10,071 while health care costs for people without diabetes amounted to $2,699 in 1997. [Information obtained from the American Diabetes Association.]
Hyperglycemia, a common feature of diabetes, is caused by decreased glucose utilization by liver and peripheral tissues and an increased glucose production by liver. Glucokinase (GK), the major glucose phosphorylating enzyme in the liver and the pancreatic xcex2-cells, plays an important role in regulating blood glucose homeostasis. Notably, the levels of this enzyme are lowered in patients with type 2 diabetes (Caro, J. F. et al., Hormone metabolic Res. 27;19-22,1995) and in some diabetic animal models (Barzilai, N. and Rossetti, L. J. Biol. Chem. 268:25019-25025). Studies involving transgenic diabetic mice have shown that increased GK copy number results in increased hepatic glucose metabolism and decreased plasma glucose levels (Ferre, T. et al., Proc. Natl. Acad. Sci. USA 93:7225-7230, 1996a and FASEB J. 10:1213-1218, 1996b; Niswender, K. D. et al., J. Biol. Chem. 272:22570-22575,1997), demonstrating that increasing liver GK may be effective in reducing hyperglycemia in diabetes. In addition, Hariharan, N. et al., (Diabetes 46:11-16, 1997) have demonstrated that increasing liver GK improves glucose homeostasis and leads to weight reduction in transgenic mice.
An approach to increase liver GK activity is to relieve its inhibition by the glucokinase regulatory protein (xe2x80x9cGKRPxe2x80x9d) (e.g. decrease GKRP expression). Van Schaftingen and coworkers were the first to identify GKRP and suggested that it might play a role in control of liver GK activity (Van Schaftingen, E. et al., Adv. Enzyme Regul. 32:133-148, 1992). They demonstrated that GKRP binds to GK and inhibits its activity and that fructose-6-phosphate (F-6-P) increases the inhibition of GK by binding to GKRP. This inhibition is reversed by the binding of fructose-1-phosphate (F-1-P) to GKRP (Vandercammen, A. et al., Biochem. J. 286:253-256, 1992 and Van Schaftingen, E. et al., FASEB J. 8:414419, 1994). Various groups have also demonstrated that GKRP binds to GK in the hepatocyte nucleus and may therefore function in vivo to regulate GK activity (Brown, K. S. et al., Diabetes 46:179-186, 1997; De la Iglesia, N. et al., FEBS Left. 456:332-338,1999; Fernandez-Novell, J. M. et al., FEBS Left. 459:211-214, 1999). The relevance of this mechanism in an in vivo setting has been demonstrated in experiments by Cherrington and coworkers (Shiota, M. et al., Diabetes 47:867-873, 1998). In these studies, small amounts of fructose, which is converted to fructose-1-phosphate in the liver and thus should increase free GK, substantially increased net hepatic glucose utilization, analogous to what is seen in the transition from fasted to fed states.
For the foregoing reasons, there is a need for new therapeutic treatments for diabetes; particularly by increasing GK activity.
There is also a need for other combinations of peptides and compounds and methods of their use for treating diabetes and diabetes-related conditions.
Toward these ends and others, in one aspect the present invention there is provided a method of treating diabetes and diabetes-related conditions comprising administering to a subject in need thereof a therapeutically effective amount of a polynucleotide sequence encoding 1) GKRP or 2) GKRP in combination with a polynucleotide sequence encoding GK.
In another aspect, the present invention provides a method of treating diabetes and diabetes-related conditions comprising administering to a subject in need thereof a therapeutically effective amount of a polynucleotide sequence encoding one or more metabolism modifying proteins and peptides in combination with a polynucleotide sequence encoding 1) GK or 2) GKRP or 3) GKRP in combination with GK. Preferred metabolism modifying proteins and peptides include uncoupling proteins 2 and 3 (xe2x80x9cUCP2 and UCP3xe2x80x9d), peroxisome proliferator-activated receptor xcex1 (xe2x80x9cPPARxcex1xe2x80x9d), the long form of the leptin receptor (xe2x80x9cOB-Rbxe2x80x9d), glucagon-like peptide 1 (xe2x80x9cGLP-1xe2x80x9d) alone or in combination with a dipeptidyl peptidase IV (xe2x80x9cDPP-IVxe2x80x9d) inhibitor and GLP-1 analogs. Preferred examples of GLP-1 analogs include GLP-1-Gly8, Extendin4, xe2x80x9cBlack Widowxe2x80x9d chimeric GLP-1 analog.
In accordance with the above aspects of the invention, additional compounds may be co-administered with the combinations of proteins and peptides. The compounds include, but are not limited to, PPARxcex1 ligands and DPP-IV inhibitors.
The diabetes and diabetes-related conditions which are treated by the above-described methods include, but are not limited to, diabetes characterized by the presence of elevated blood glucose levels, such as hyperglycemic disorders, for example, diabetes mellitus, including both type 1 and type 2 diabetes as well as other diabetic-related disorders such as obesity, increased cholesterol, kidney-related disorders, decreased liver GK activity and the like. The above-described methods may be employed to lower insulin levels, improve glucose tolerance, increase hepatic glucose utilization, normalize blood glucose levels, increase apo A-I and HDL levels, decrease fibrinogen levels, stimulate hepatic fatty acid oxidation, reduce hepatic triglyceride accumulation and normalize glucose tolerance.
In another aspect the present invention provides a vector comprising a polynucleotide sequence(s) encoding GKRP or GKRP in combination with GK. In another embodiment of this aspect of the invention there is provided a vector comprising a polynucleotide sequence(s) encoding one or more metabolism modifying proteins and peptides in combination with a polynucleotide sequence encoding 1) GK or 2) GKRP or 3) GKRP in combination with GK.
In accordance with yet another aspect of the present invention there is provided a method of expressing 1) GKRP or 2) GKRP in combination with GK, comprising transducing cells in vivo with a vector comprising a polynucleotide sequence(s) encoding 1) GKRP or 2) GKRP in combination with GK, such that the cells are modified to produce the respective proteins and peptides.
In accordance with still another aspect of the present invention there is provided a method of expressing one or more metabolism modifying proteins and peptides in combination with 1) GK or 2) GKRP or 3) GKRP in combination with GK, comprising transducing cells in vivo with a vector comprising a polynucleotide sequence(s) encoding one or more metabolism modifying proteins and peptides in combination with a polynucleotide sequence encoding 1) GK or 2) GKRP or 3) GKRP in combination with GK, such that the cells are modified to produce the respective proteins and peptides.
In accordance with still another aspect of the present invention there is provided a pharmaceutical composition comprising vectors comprising a polynucleotide sequence(s) encoding 1) GKRP or 2) GKRP in combination with GK and a pharmaceutically acceptable carrier suitable for administration to a subject. In accordance with this aspect of the invention there is provided a pharmaceutical composition comprising vectors comprising a polynucleotide sequence(s) encoding one or more metabolism modifying proteins and peptides in combination with a polynucleotide sequence encoding 1) GK or 2) GKRP or 3) GKRP in combination with GK and a pharmaceutically acceptable carrier suitable for administration to a subject.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill from the following description, appended claims and accompanying drawings. It should be understood, however, that the following description, appended claims, drawings and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.